EP1889846A1 - Purinderivate als A2a Agonisten - Google Patents

Purinderivate als A2a Agonisten Download PDF

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Publication number
EP1889846A1
EP1889846A1 EP06117168A EP06117168A EP1889846A1 EP 1889846 A1 EP1889846 A1 EP 1889846A1 EP 06117168 A EP06117168 A EP 06117168A EP 06117168 A EP06117168 A EP 06117168A EP 1889846 A1 EP1889846 A1 EP 1889846A1
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EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
purin
group
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP06117168A
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English (en)
French (fr)
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designation of the inventor has not yet been filed The
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Novartis AG
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Novartis AG
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Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Priority to EP06117168A priority Critical patent/EP1889846A1/de
Priority to US12/308,637 priority patent/US8071565B2/en
Priority to BRPI0714216-1A priority patent/BRPI0714216A2/pt
Priority to JP2009518788A priority patent/JP2009542753A/ja
Priority to CN2007800240198A priority patent/CN101479267B/zh
Priority to KR1020097000552A priority patent/KR20090016017A/ko
Priority to EP07765174A priority patent/EP2044070B1/de
Priority to MX2009000375A priority patent/MX2009000375A/es
Priority to PCT/EP2007/006156 priority patent/WO2008006563A1/en
Priority to AU2007271944A priority patent/AU2007271944A1/en
Priority to RU2009104764/04A priority patent/RU2009104764A/ru
Priority to CA002656012A priority patent/CA2656012A1/en
Priority to ES07765174T priority patent/ES2393931T3/es
Publication of EP1889846A1 publication Critical patent/EP1889846A1/de
Priority to ZA200810671A priority patent/ZA200810671B/xx
Priority to CR10520A priority patent/CR10520A/es
Priority to TNP2008000544A priority patent/TNSN08544A1/en
Priority to IL196330A priority patent/IL196330A0/en
Priority to GT200900007A priority patent/GT200900007A/es
Priority to EC2009009063A priority patent/ECSP099063A/es
Priority to MA31615A priority patent/MA30693B1/fr
Priority to NO20090664A priority patent/NO20090664L/no
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • An aspect of the present invention provides compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, wherein W is CH 2 or O, with the proviso that when W is O, then R 1 is not a N-bonded substituent;
  • R 1 is suitably a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • R 1 is a 5-membered heterocyclic group, such as pyazole, triazole, tetrazole, isoxazole and imidazole-2,4-dione.
  • These heterocyclic groups are suitably substituted by a C 1 -C 8 -alkyl optionally substituted by OH.
  • the heterocyclic groups can be either N-bonded or C-bonded.
  • the heterocyclic groups pyrazole, triazole, tetrazole and imidazole-2,4-dione are suitably N-bonded when attached to a cyclopentane group (e.g., when W is CH 2 ).
  • These N-bonded heterocyclic groups can also be suitably substituted by groups such as methanol, methyl, ethyl, methoxy and methoxy-methyl.
  • the R 1 groups attached to the cyclopentane group are
  • the heterocyclic groups isoxazole and tetrazole are C-bonded when attached to a furan group (e.g., when W is O). These C-bonded heterocyclic groups are suitably substituted by C 1 -C 8 -alkyl optionally substituted by OH such as hydroxymethyl, hydroxyethyl, an ethyl group or a methyl group.
  • the R 1 groups attached to the furan group are
  • R 2 is suitably selected from C 1 -C 8 -alkyl optionally substituted by OH, halogen or C 6 -C 10 -aryl optionally substituted by OH, halogen, such as Cl or O-C 1 -C 8 -alkyl, preferably C 6 -C 10 aryl is phenyl. Also, preferably, the C 1 -C 8 -alkyl is substituted by two phenyl rings and the phenyl rings are unsubstituted or substituted by OH. Preferred R 2 groups are
  • R 3 is suitably NR 3f C(O)NR 3g R 3h .
  • R 3f and R 3h are suitably H.
  • this 3- to 12-membered heterocyclic group is a 5-membered heterocyclic group, such as tetrazole.
  • R 3g is also suitably 3- to 12-membered heterocyclic group, preferably a pyridine, containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by 0-3R 4 .
  • R 3 is also suitably NHC(O)R 3q , where R 3q is a C 6 -C 10 -aryl optionally substituted by OH, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, SO 2 R 5 or -halogen.
  • R 3q is also suitably a C 7 -C 14 -aralkyl optionally substituted by OH, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, SO 2 R 5 or -halogen.
  • Another aspect of the invention provides compounds of formula (I) wherein the compound is of formula (Ia) where R 1 is selected from R 2 is selected from and R 3 is selected from
  • Another aspect of the invention provides compounds of formula (I) wherein the compound is of formula (lb) where R 1 is selected from R 2 is selected from and R 3 is selected from
  • Stereoisomers are those compounds where there is an asymmetric carbon atom.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g., as diastereomeric mixtures.
  • the present invention embraces both individual optically active R and S isomers, as well as mixtures thereof.
  • Individual isomers can be separated by methods well-known to those skilled in the art, e.g. chiral high performance liquid chromatography (HPLC).
  • Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol.
  • solvent molecules e.g., ethanol.
  • hydrate is employed when said solvent is water.
  • Another embodiment of the present invention provides a process for the preparation of compounds of formula (I) in free or pharmaceutically acceptable salt form, which comprises the steps of:
  • the compound of formula (Ic) may be prepared by reacting a compound of formula (Ie) wherein R 1 and Z are as defined hereinbefore; and L represents a leaving group or a protected derivative thereof with a 2,6-dihalopurine, e.g., 2,6-dichloropurine, to provide a compound of formula (If) wherein R 1 and Z are defined hereinbefore; and X and X 2 are halogen.
  • a 2,6-dihalopurine e.g., 2,6-dichloropurine
  • the compounds of formula (I) can be prepared, e.g., using the reactions and techniques described below and in the Examples.
  • the compounds of formula (I) can be prepared analogously to the preparations described in Applicant's patent applications PCT/EP2005/011344 , GB 0500785.1 , and GB 0505219.6 .
  • the reactions may be performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • Compounds of formula (I) in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
  • Compounds of formula (I) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, may be obtained in a conventional manner, e.g., by fractional crystallization or asymmetric synthesis from correspondingly asymmetrically substituted, e.g., optically active, starting materials.
  • Compounds of formula (I) and their pharmaceutically acceptable salts are useful as pharmaceuticals.
  • they activate the adenosine A 2A receptor, i.e., they act as A 2A receptor agonists.
  • Their properties as A 2A agonists may be demonstrated using the method described by L. J. Murphree et al in Mol Pharmacol, Vol. 61, pp. 455-462 (2002) .
  • K i values below 1.0 ⁇ M in the above assay For example, the compounds of Examples C1 and C2 have K i values of 0.089 ⁇ M and 0.033 ⁇ M respectively.
  • agents of the invention are useful in the treatment of conditions which respond to the activation of the adenosine A 2A receptor, particularly inflammatory or allergic conditions. Treatment in accordance with the invention may be symptomatic or prophylactic.
  • agents of the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, e.g., in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression.
  • Inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular, other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis including, e.g., aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • asthma inflammatory or obstructive airways diseases to which the present invention is applicable
  • asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • agents of the invention are also useful in the treatment of eosinophil related disorders, e.g., eosinophilia, in particular, eosinophil-related disorders of the airways (e.g., involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs, as well as, e.g., eosinophil-related disorders of the airways consequential or concomitant to Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned
  • eosinophil related disorders e.g., eosinophilia, in
  • Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, e.g., psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • Agents of the invention may also be used for the treatment of other diseases or conditions, in particular, diseases or conditions having an inflammatory component, e.g., treatment of diseases and conditions of the eye, such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (
  • agents of the invention may also be used for the treatment of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, inflammatory bowel syndrome, wound healing, diabetic nephropathy as described in WO 05/107463 , reduction of inflammation in transplanted tissue as described in US 2005/182018 , inflammatory diseases caused by pathogenic organisms as described in WO 03/086408 , and cardiovascular conditions as described in WO 03/029264 .
  • the agents of the invention may be used to assess the severity of coronary artery stenosis as described in WO 00/078774 and useful in conjunction with radioactive imaging agents to image coronary activity and useful in adjunctive therapy with angioplasty as described in WO 00/78779 .
  • Agents of the invention are also useful in combination with a protease inhibitor for prevention of organ ischemia and reperfusion injury as described in WO 05/003150 , and in combination with an integrin antagonist for treating platelet aggregation as described in WO 03/090733 .
  • Agents of the invention are also useful in promoting wound healing in bronchial epithelial cells as described in AJP-Lung, Vol. 290, pp. 849-855 .
  • diabetes e.g., diabetes mellitus type I (juvenile diabetes) and diabetes mellitus type II, diarrheal diseases, ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma, ischemic tissue/organ damage from reperfusion and bedsores.
  • diabetes mellitus type I juvenile diabetes
  • diabetes mellitus type II diarrheal diseases
  • ischemia/reperfusion injuries retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy
  • retinopathy such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy
  • conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor such as glaucoma, ischemic tissue/organ damage from reperfusion and bedsores.
  • an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g., a mouse or rat model, of airways inflammation or other inflammatory conditions, e.g., as described by Szarka et al, J Immunol Methods, Vol. 202, pp. 49-57 (1997) ; Renzi et al, Am Rev Respir Dis, Vol. 148, pp. 932-939 (1993) ; Tsuyuki et al., J Clin Invest, Vol. 96, pp. 2924-2931 (1995) ; Cernadas et al., Am J Respir Cell Mol Biol, Vol. 20, pp. 1-8 (1999) ; and Fozard et al, Eur J Pharmacol, Vol. 438, pp. 183-188 (2002) .
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular, glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167 , WO 02/12266 , WO 02/100879 , WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668 , WO 03/48181 , WO 03/62259 , WO 03/64445 , WO 03/72592 , WO 04/39827 and WO 04/66920 ; non-steroidal glucocorticoid receptor agonsts, such as those described in DE 10261874 , WO 00/00531 , WO 02/10143 , WO 03/82280 , WO 03/82787 , WO
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , US 3714357 , US 5171744 , US 2005/171147 , US 2005/182091 , WO 01/04118 , WO 02/00652 , WO 02/51841 , WO 02/53564 , WO 03/00840 , WO 03/33495 , WO 03/53966 , WO 03/87094 , WO 04/018422 , WO 04/05285 and WO 05/077361 .
  • anticholinergic or antimuscarinic agents in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also
  • Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as those disclosed in US 2004/0167167 , US 2004/0242622 , US 2005/182092 , WO 04/74246 and WO 04/74812 .
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299 , WO 03/099807 and WO 04/026841 .
  • agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists, such as N -[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5 H -benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro- N,N- dimethyl-2 H -pyran-4-amin-ium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8
  • the invention also provides a method for the treatment of a condition responsive to activation of the adenosine A 2A receptor, e.g., an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt.
  • a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to activation of the adenosine A 2A receptor, particularly an inflammatory or obstructive airways disease.
  • the agents of the invention may be administered by any appropriate route, e.g., orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of inflammatory or obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin, e.g., in the treatment of atopic dermatitis; or rectally, e.g., in the treatment of inflammatory bowel disease.
  • routes e.g., orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of inflammatory or obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin, e.g., in the treatment
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compounds of formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • the composition may contain a co-therapeutic agent, such as an anti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • a co-therapeutic agent such as an anti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations
  • the composition comprises an aerosol formulation
  • it preferably contains, e.g., a hydro-fluoro-alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art, such as ethanol (up to 20% by weight), and/or one or more surfactants, such as oleic acid or sorbitan trioleate, and/or one or more bulking agents, such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, e.g., the compounds of formula (I) having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g., magnesium stearate.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, e.g., the compound of formula (I) either dissolved, or suspended, in a vehicle containing water, a co-solvent, such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.
  • the invention includes:
  • Dosages of compounds of formula (I) employed in practicing the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg, while for oral administration suitable daily doses are of the order of 0.05-100 mg.
  • Phenyl chloroformate (0.733 mL, 5.84 mmol) is suspended in pyridine/DCM (3 mL, 2:1). The solution is stirred at 0°C, and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 mL) is added dropwise. The reaction mixture is at 0°C for 1 hour. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. This organic portion is washed with 0.1 M HCl and then concentrated in vacuo to afford the titled compound. (MH+ 215)
  • Step CA1 Acetic acid (2 R ,3 R ,4 R ,5 S )-4-acetoxy-2-[6-(( S )-1-benzyl-2-hydroxy-ethyl amino)-2-chloro-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3-yl ester hydrochloride
  • Step CA2 (2 R ,3 R ,4 S ,5 S )-2-[6-(( S )-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol
  • Step CD1 Acetic acid (2 R ,3 R ,4 R ,5 R )-4-acetoxy-2-[6-(( S )-1-benzyl-2-hydroxy-ethyl amino)-2-chloro-purin-9-yl]-5-(2-ethyl-2 H -tetrazol-5-yl)-tetrahydro-furan-3-yl ester
  • Step CD2 (2 R ,3 R ,4 S ,5 R )-2-[6-(( S )-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol
  • Step CD1 analogously to (2 R ,3 R ,4 S ,5 S )-2-[6-(( S )-1-benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol (Step CA2).
  • Step CG1 Acetic acid (2 R ,3 R ,4 R ,5 S )-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3-yl ester
  • Step CG2 (2 R ,3 R ,4 S ,5 S )-2-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol
  • the title compound is prepared from acetic acid (2 R ,3 R ,4 R ,5 S )-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3-yl ester ( WO 99/38877 ) analogously to (2 R ,3 R ,4 S ,5 S )-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol (Intermediate CG) by replacing 2,2-diphenylethylamine with 4,4'-(2-aminoethylidene)bis-phenol (Intermediate A).
  • the title compound is prepared from acetic acid (2 R ,3 R ,4 R ,5 S )-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3-yl ester ( WO 99/38877 ) analogously to (2 R ,3 R ,4 S ,5 S )-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol (Intermediate CG ) by replacing 2,2-diphenylethylamine with ( S )-2-amino-3-phenyl-propan-1-ol.
  • the title compound is prepared in an analogous fashion to (2 R ,3 S ,4 R ,5 R )-2-(2-benzyl-2 H -tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol ( WO 99/38877 ) by replacing 2,2-diphenylethylamine with ( S )-2-amino-3-phenyl-propan-1-ol.
  • Example 1 1-(( R )-1- ⁇ 6-(2,2-Diphenyl-ethylamino)-9-[(2 R ,3 R ,4 S ,5 R )-5-(2-ethyl-2 H- tetrazol-5-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-9 H -purin-2-yl ⁇ -pyrrolidin-3-yl)-3-(3-hydroxy-benzyl)-urea trifluoroacetate
  • Step 1 (2 R ,3 R ,4 S ,5 R )-2-[6-(2,2-Diphenyl-ethylamino)-2-(( R )-3-BOC-amino-pyrrolidin-1-yl)-purin-9-yl]-5-(2-ethyl-2 H -tetrazol-5-yl)-tetrahydro-furan-3,4-diol
  • the reaction mixture is heated using microwave radiation at 160°C for 30 minutes in the Personal Chemistry EmrysTM Optimizer microwave reactor.
  • the reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile:water (0.1% TFA) (gradient 0-100% acetonitrile) to afford the titled compound.
  • Step 2 (2 R ,3 R ,4 S ,5 R )-2-[2-(( R )-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2 H -tetrazol-5-yl)-tetrahydro-furan-3,4-diol trifluoroacetate
  • Step 3 1-(( R )-1- ⁇ 6-(2,2-Diphenyl-ethylamino)-9-[(2 R ,3 R ,4 S ,5 R )-5-(2-ethyl-2 H -tetrazol-5-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-9 H -purin-2-yl ⁇ -pyrrolidin-3-yl)-3-(3-hydroxy-benzyl)-urea trifluoroacetate
  • Example 2 These are prepared analogously to Example 1 by combining the appropriate starting compound from Table 1a (Intermediates CA-CI ) with the appropriate phenyl esters (Intermediates BA-BD ).
  • Example 37 1- ⁇ ( R )-1-[9- ⁇ (2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-[2-(2-hydroxy-ethyl)-2 H- tetrazol-5-yl]-tetrahydro-furan-2-yl ⁇ -6-(2,2-diphenyl-ethylamino)-9 H- purin-2-yl]-pyrrolidin-3-yl ⁇ -3-(3-hydroxy-benzyl)-urea
  • Step 1 1- ⁇ ( R )-1-[9-[(2 R ,3 R ,4 S ,5 R )-5-(2-Benzyl-2 H -tetrazol-5-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea
  • This compound is prepared from (2 R ,3 S ,4 R ,5 R )-2-(2-benzyl-2 H -tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol ( WO 99/38877 ) and pyridin-3-yl-carbamic acid phenyl ester (Intermediate BB ) analogously to Example 1.
  • Step 2 1- ⁇ ( R )-1-[9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(2 H -tetrazol-5-yl)-tetrahydro-furan-2-yl]-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea
  • Step 3 1- ⁇ ( R )-1-[9- ⁇ (2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-[2-(2-hydroxy-ethyl)-2 H -tetrazol-5-yl]-tetrahydro-furan-2-yl ⁇ -6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea
  • Step a (1 S ,4 R )-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enol
  • 2,6-Dichloropurine (10 g, 52.90 mmol), (1 S ,4 R )- cis -4-acetoxy-2-cyclopenten-1-ol (10g, 70.40 mmol), tris (dibenzylideneacetone)dipalladium(0) (3.20 g, 3.50 mmol) and polymer supported triphenylphosphine (3 mmol/g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (80 mL) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at 50°C.
  • Step b Carbonic acid (1 S ,4 R )-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester
  • step1 (1 S ,4 R )-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enol [step1] (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (200 mL) is added followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is added slowly so that the temperature does not rise above 40°C and the reaction mixture is stirred at RT. The reaction is shown to be complete by LCMS after 2 hours.
  • Step e ⁇ ( R )-1-[9-((1 R ,2 S ,3 R ,4 S )-4-Benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -carbamic acid tert-butyl ester
  • Step f ⁇ (1 S ,2 R ,3 S ,4 R )-4-[2-(( R )-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -carbamic acid benzyl ester
  • Step a ⁇ 1-[(1 S ,4 R )-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enyl]-1 H -pyrazol-4-yl ⁇ -methanol
  • Step b (1- ⁇ (1 S ,4 R )-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ⁇ -1 H -pyrazol-4-yl)-methanol
  • a mixture comprising ⁇ 1-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-1H-pyrazol-4-yl ⁇ -methanol (0.675 g, 1.92 mmol), diphenylethylamine (0.398 g, 2.02 mmol) and DIPEA (0.298 g, 2.31 mmol) in dry THF (20 mL) is stirred at 35°C for 3 days. The solvent is removed in vacuo and the resulting crude residue is partitioned between DCM and 0.1 M HCl. The organic portion is separated, washed with water, brine, dried (MgSO 4 ) and concentrated in vacuo to afford the title product.
  • Step d (1 R ,2 S ,3 R ,5 S )-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol
  • This compound is prepared from 4-aminobenzenesulphonamide using a procedure analogous to that of 3-isocyanato-benzenesulfonamide (Intermediate 5) by replacing 3-aminobenzenesulphonamide with 4-aminobenzenesulphonamide.
  • Example C1 1- ⁇ ( R )-1-[9-[(1 R ,2 S ,3 R ,4 S )-4-(2,5-Dioxo-imidazolidin-1-yl)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea
  • Step 1 ((1 S ,2 R ,3 S ,4 R )-4- ⁇ 6-(2,2-Diphenyl-ethylamino)-2-[( R )-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-carbamic acid benzyl ester trifluoroacetate
  • Step 2 1- ⁇ ( R )-1-[9-((1 R ,2 S ,3 R ,4 S )-4-Amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea
  • Step 3 1- ⁇ ( R )-1-[9-[(1 R ,2 S ,3 R ,4 S )-4-(2,5-Dioxo-imidazolidin-1-yl)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea hydrochloride
  • Example C2 1- ⁇ ( R )-1-[9-[(1 R ,2 S ,3 R ,4 S )-4-(2,5-Dioxo-imidazolidin-1-yl)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -3-pyridin-3-yl-urea trifluoroacetate
  • This compound is prepared analogously to Example 1 by replacing Z-L-alanine hydroxysuccinimidyl ester (Step 3) with Z-glycine- N -succinimidyl ester. Purification is carried out by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1% TFA). [MH+718.68].
  • 3-hyroxybenzyl groups are prepared as follows: (3-hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate BA ) and (Intermediate 2 , 7 or 8 ) are dissolved in MeOH and TEA. The reaction mixture is heated using microwave radiation at 100°C for 30 minutes and then the solvent is removed in vacuo. Purification of the crude product by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1 % TFA) affords the product which is taken through Steps 2 and 3 (using the appropriate succinimidyl ester) to afford the final compound.
  • Step 1 ⁇ ( R )-1-[6-(2,2-Diphenyl-ethylamino)-9 H -purin-2-yl]-pyrrolidin-3-yl ⁇ -carbamic acid tert-butyl ester
  • Step 2 ⁇ ( R )-1-[6-(2,2-Diphenyl-ethylamino)-9-((1 R ,4 S )-4-hydroxy-cyclopent-2-enyl)-9 H- purin-2-yl]-pyrrolidin-3-yl ⁇ -carbamic acid tert-butyl ester
  • Step 3 Carbonic acid (1 S ,4 R )-4-[2-(( R )-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester
  • Step 4 (( R )-1- ⁇ 6-(2,2-Diphenyl-ethylamino)-9-[(1 R ,4 S )-4-(5-ethyl-tetrazol-2-yl)-cyclopent-2-enyl]-9 H -purin-2-yl ⁇ -pyrrolidin-3-yl)-carbamic acid tert-butyl ester
  • Step 5 (( R )-1- ⁇ 6-(2,2-Diphenyl-ethylamino)-9-[(1 R ,4 S )-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9 H -purin-2-yl ⁇ -pyrrolidin-3-yl)-carbamic acid tert-butyl ester
  • Step 6 3-[3-(( R )-1-(6-[bisphenyl-ethylamino]-9-[(1 R ,2 S ,3 R ,4 S )-2,3-dihydroxy-4-(5-ethyltetrazol-2-yl)-cyclopentyl]9 H -purin-2-yl ⁇ -[yrrolidin-3-yl)-ureido]-benzenesulphonamide
  • Example C1 The title compound is then prepared in an analogous manner to Example C1, Step 1 by replacing ⁇ (1 S ,2 R ,3 S ,4 R )-4-[2-(( R )-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -carbamic acid benzyl ester with the above free amine and replacing pyridine-3-isocyanate with Intermediate 5 .
  • Examples of the structure XYZ are prepared in a multiparallel sequence of reactions as described below.
  • Heterocycles X-H are prepared as follows:

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